Uterine contractility is of crucial importance for reproduction in mammals, and its proper regulation is necessary at all stages of pregnancy. Uterine function is characterized by spontaneous contractile activity dependent on smooth muscle cell pacemaker activity. Spike-like action potentials trigger contractile activity by influx of extracellular Ca 2+ and the release of Ca2+ from intracellular stores. The changes in membrane electrical charge are reflected in changes in contractility. The regularity and power of uterine contractions depend on the conductance of the electrical signal and are determined by intercellular contacts. Activation of PAR-2 has been shown to induce contraction in various types of smooth muscles, but little is known regarding the effect of PAR-2 activation on uterine smooth muscle. Our preliminary studies demonstrated that the PAR-2 agonist trypsin activates contractility of isolated uterine tissues from term pregnant rats and women, suggesting a potential role for PAR-2 in parturition. The general hypothesis of the proposed study is that PAR-2 plays an important role in labor, that expression of PAR-2 depends on gestational age and that PAR-2 modulates uterine responsiveness to stimulatory and inhibitory agents. The specific aims are 1) to determine the expression of PAR-2 mRNA and protein in the myometrium from non-pregnant, early-pregnant, mid-pregnant, and term-pregnant rats, as well as in the myometrium obtained from term pregnant women before and after the onset of labor; 2) to investigate whether contractile responses to PAR-2 activation depend on the gestational age in isolated rat uterine tissues and on the non-labor labor state in human myometrial tissues; 3) to evaluate whether PAR-2- mediated contractility involves uterotonic mediators (prostaglandins, thromboxane, platelet activating factor). The potential benefits of these studies include a better understanding of the mechanisms modulating uterine contractility, thereby improving our ability to control it clinically. [unreadable] [unreadable]